The purpose of this Physician Scientist Award is to prepare the applicant for a career as an independent investigator in medical science. Toward this end, the two phases have been carefully designed to provide a broad didactic exposure to the relevant areas of basic science, an in depth experience with the laboratory techniques involved, and most importantly, an apprenticeship in the process of scientific inquiry. During Phase I, the candidate will undertake graduate level coursework in molecular genetics and immunology at Harvard University and MIT. These courses have been carefully selected to provide the fundamental background necessary as a springboard for the proposed investigations. Simultaneously, laboratory experience will begin under the supervision of Dr. Jonathan Seldman, the Phase I sponsor, Dr. Seldman has been chosen not only because of his important contributions to the molecular biology of T lymphocytes but also because of his enthusiasm for and proven ability to help clinically trained fellows mature into independent investigators. The proposed research is directed at an improved understanding of the cells that mediate transplant rejection and ultimately at finding ways of better controlling that process. Specifically, during Phase I, the candidate plans to learn techniques of recombinant DNA technology and cellular immunology in Dr. Seldman's laboratory and then apply these techniques to biopsy samples from cardiac transplant patients. T lymphocytes from endomyocardial biopsies will be cloned and them expanded in culture. The expanded clones will then be analyzed for phenotypic subset, antigen reactivity, cytotoxicity, lymphokine production, and the presence of T cell receptor gene rearrangements. A research advisory committee, selected by Dr. Seldman and Dr. John Potts, Chief of Medicine at MGH, will review the candidate's progress during Phase I. This committee will help guide the candidate toward his goal of learning the process off scientific inquiry. The committee will also facilitate the timing of, and the transition to, Phase II of the award. In Phase II, Phase I results concerning the lymphocytes involved in transplant rejection and the epitopes against which they are directed will be used to direct further research aimed ultimately at specifically modulating the host's immune response. Antibodies to the receptors of important T cell clones could be sought , as well as "inhibitory peptides" for important epitopes. Eventually, studies performed in the transplant model because of tissue availability would be extended to other inflammatory cardiovascular conditions such as myocarditis, rheumatic carditis, Chagas disease, or vasculitis.